The use of biodegradable polymers in medical applications, such as sutures, staples, surgical clips, implant and drug delivery systems, is well known. A particular use is the in situ formation of biodegradable implants or inserts; in this application, the term "biodegradable implant" and "biodegradable insert" will be used interchangeably. The in situ formation of biodegradable implants is described, for example, in U.S. Pat. No. 4,938,763; Duysen et al., Pharmaceutical Research, 1994, Amer. Assoc. of Pharm. Scientists, Presentation #7575; Frank et al., Pharmaceutical Research, 1994, Amer. Assoc. of Pharm. Scientists, Presentation #2070; Dunn et al., Proc. Int. Symp. Control. Rel. Bioact. Mater., 22 (1995); Dunn et al., Portland Bone Symposium, Aug. 2-5, 1995, Portland, Oreg.; Andreopoulos, Clinical Materials 15 (1994) 89-92; Lambert & Peck, J. Controlled Release 33 (1995) 189-195; Shah et al., J. Controlled Release 27 (1993) 139-147; Shively et al., J. Controlled Release 33 (1995) 237-243; Lowe et al., 19th Ann. Mtg. Soc. Biomaterials.
Such implants serve two main purposes: as space-filling material, e.g. where tissue has been removed or where bone regeneration is required; and as a mechanism for controlled release of drugs. The advantages of forming such inserts in situ as opposed to outside the body are described in the foregoing references, and include the ability to insert the implant without resorting to surgery, as well as the capability of the implant to be formed exactly to the dimensions of the cavity being filled when space-filling is the goal of the implant.
As described in U.S. Pat. No. 4,938,763, one of the methods (the "thermoplastic system") which may be employed for the in situ formation of implants is the injection of a solution containing a water-immiscible biodegradable polymer and a water-miscible biologically compatible (non-toxic) solvent into an animal. The solvent is quickly carried away from the injection site, and the polymer left behind in the aqueous environment of the body quickly coagulates or solidifies into a solid matrix structure. If the implant is meant to serve as a drug-delivery system, then the drug is incorporated into the solution prior to injection, and is trapped in the solid matrix formed upon coagulation of the polymer. As will be appreciated by persons skilled in the art, different degrees of coagulation, and thus different rates of biodegradation and/or, if applicable, drug release, may be achieved, by varying the characteristics of the polymer or copolymer (e.g., degree of hydrophobicity or average molecular weight), the solvent, and the relative amount of each component prior to injection. The relative amount of the drug and the identity of the drug are also important factors when the implant serves as a controlled-release device.
The polymers and copolymers known in the art to be suitable for use in the "thermoplastic method" of in situ implant formation disclosed in U.S. Pat. No. 4,938,763 include poly(L-lactic acid), poly(D-lactic acid), poly(DL-lactic acid), poly(L-lactide), poly(D-lactide), poly(DL-lactide), poly(DL-lactide-co-glycolide), poly(lactic-co-glycolic) acid, polyglycolide, and polyglycolic acid. Solvents known in the art include N-methyl pyrrolidone, propylene glycol, triacetin, triethyl citrate, and dimethyl sulfoxide. As stated, it will be appreciated that the degree of coagulation of the polymer, and thus the rate of biodegradation and/or drug release, is dependent in part on the choice of solvent used. On the other hand, the ability of a given biocompatible solvent to dissolve a given biodegradable polymer, and to provide a solution that can be used in a method for the in situ formation of a biodegradable polymeric implant is, at best, unpredictable. Not every biocompatible solvent can be used with any given biodegradable polymer, and not every biodegradable polymer can be used with any given solvent to provide the desired solution for use in in situ formation of a biodegradable polymeric implant. Furthermore, in view of the fact that, ultimately, the above biocompatible solvent-biodegradable polymer containing solutions are intended for administration in humans, it is essential that such solutions be acceptable pharmacologically, i.e., that their administration will be essentially harmless to the patient. Likewise, in veterinary medicine, when such implants are to be formed in, for example, domestic animals, it is essential that the solutions administered to the animals are essentially harmless.
Accordingly, in view of the above-mentioned medical and veterinary considerations, the number of potential biocompatible solvent-biodegradable polymer combinations useful for administration to humans and/or animals for in situ biodegradable implant formation is considerably restricted. One of the drawbacks of the prior art noted above is the general failure to provide specific, harmless solutions that can be used for the in situ formation of biodegradable polymers; often, at least some of the polymers to be dissolved therewith are not suitable for human or animal administration.
Another drawback of the above prior art is that often, when a desirable solvent-polymer combination is obtained that is fit for medical and/or veterinary use, the process by which such a combination, i.e., solution, is produced is often tedious, requiring special conditions for production. For example, in the above-noted U.S. Pat. No. 4,938,763, there are described various methods for preparing some solvent-polymer combinations for use as in situ forming biodegradable implants, many of which methods require the use of catalysts, more than one solvent, high temperatures and other special conditions to provide the solvent-polymer solution to be administered.
Poly(lactic-co-glycolic acid) copolymer (PLGA) is used for injection in man and used for parenteral applications. Glycofurol (.alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl)) is used as a solvent in parenteral products for intravenous or intramuscular injection of concentrations of up to 50% v/v; when administered parenterally to humans, quantities of glycofurol should not exceed 0.07 ml per kg of body weight per day (Handbook of Pharmaceutical Excipients, Am. Pharmac. Assoc. and Pharm. Soc. of Gr. Br., 1994). However, heretofore, there has not been described a solution useful for the in situ formation of a biodegradable implant that is comprised of a biocompatible solvent being glycofurol and a biodegradable polymer being composed of lactic acid (LA) and/or glycolic acid (LG) units, e.g. PLGA, of which both polymer and solvent have been approved for human administration, and which are compatible with each other, such that the polymer may be readily dissolved in the solvent at room temperature, without the need for other additives such as catalysts, additional solvents or the like; and which solution is useful for the in situ formation of a biodegradable implant for tissue or bone replacement, and for the controlled release of drugs.
It is therefore an object of the invention to provide a composition comprising a polymer which is PLGA containing from 10-100 wt. % lactic acid (LA) units, preferably from 50-90 wt. % LA units, and a solvent which is glycofurol for use in the formation of a biodegradable implant.
It is another object of the invention to provide a method which employs the composition of the invention in the in situ formation of a biodegradable implant.
It is yet another object of the invention to provide biodegradable polymeric implants which can be as controlled-delivery devices for drugs or other biologically active agents.
It is another object the invention to provide implants the properties of which may be manipulated so as to enable the use of said implants with both hard and soft tissues.
It is still another object of the invention to provide biodegradable polymeric implants comprising as polymer PLGA containing from 10-100 wt. % LA units, preferably 50-90 wt. % LA units, whenever prepared from the composition of the invention or by the method of the invention.
Other objects of the invention will become apparent as the description proceeds.